Experimental Autoimmune Myocarditis Produced by Adoptive Transfer of Splenocytes After Myocardial Infarction

Abstract

One possible mechanism for neurohumoral activation after myocardial infarction may be the generation of an immune response against cardiac self-antigens. We hypothesize that if there is a T cell-mediated reaction to self-antigens, the transfer of splenic lymphocytes from postinfarct rats into syngeneic rats with normal hearts should result in a T cell-mediated autoimmune myocarditis in the healthy syngeneic rats. Rats were killed 6 weeks after coronary ligation. Splenocytes from animals with large and small infarcts were purified from spleens, activated with concanavalin A, and injected in varying doses into normal syngeneic rats. These recipient rats were killed 6 weeks later, and histopathological studies were performed. Our results demonstrate in vivo evidence of lymphocyte-mediated myocardial injury by adoptive transfer of sensitized lymphocytes from rats who developed congestive heart failure after acute myocardial infarction. The amount of infiltrate and necrosis in the recipient rats appeared directly related to the size of the infarct from the donor rats. This suggests that larger infarcts lead to a greater inflammatory response as well as a greater propensity for alteration of cardiac surface antigens or the emergence of previously sequestered antigens. None of the other organs (kidney, liver, lung, or brain) had evidence of infiltrates. Two-dimensional echocardiography did not reveal systolic dysfunction. This study provides direct evidence of autoimmune myocardial injury produced by adoptive transfer of concanavalin A-activated splenocytes after myocardial infarction. We propose that neurohumoral activation early in the postinfarction period triggers a series of specific inflammatory and immunological events that lead to formation of specific clones of T cells. When these are activated and transferred into normal rats, cardiac-specific cellular infiltration occurs, occasionally accompanied by myocardial necrosis. This model should help to further explore the link between neurohumoral activation after myocardial infarction and the subsequent immune alterations that might be associated with the development and/or progression of congestive heart failure. Additionally, this might be a useful model in which to study other immune-mediated cardiomyopathies.

Identification of Noncytotoxic and IL-10–Producing CD8+AT2R+ T Cell Population in Response to Ischemic Heart Injury

“…Indeed, there is clear evidence showing that an inflammatory reaction can severely augment postinfarct cardiac damages (1,2). For example, postinfarct splenic CD8 + T lymphocytes exert cytotoxicity to healthy CMs (2), and adoptive transfer of postinfarct splenic lymphocytes results in adaptive autoimmune myocarditis in recipient rats (1).…”

“…For instance, experimental studies demonstrated that CD8 + T cells derived from rats with MI are cytotoxic to healthy cardiomyocytes (CMs), and adoptive transfer of postinfarct splenic lymphocytes results in T cell-mediated myocardial injury in recipient rats (1,2). It is proposed that ischemia-induced myocardial necrosis releases or exposes normally sequestered constituents that may trigger an autoimmune response in the myocardium, as evidenced by clinical observations that autoantibodies against cardiac contractile proteins are indeed detectable in the sera of patients after MI (3).…”

Toward a broader understanding of aldosterone in congestive heart failure

“…42,43 The interrogation of complex molecular events that account for immune cell activation and subsequent homing of these cells to the heart, may explain why cardiac pathology does not appear until week 4 of ALDOST and calls into question the prospect of an autoimmune response, not unlike that which can follow myocardial infarction (MI). 73 In rodents treated with a Mg 2+ -deficient diet, a putative state of exaggerated aldosteronism (see above), lymphocyte Mg 2+ is reduced to an extent comparable to the Mg 2+ depletion that appears in skeletal muscle and cardiac tissue. 74 Weglicki and co-workers have identified an early (week 1) induction of oxi/nitrosative stress and depletion of antioxidant defences in PBMC and endothelial cells.…”

Differential Effects of GM-CSF and G-CSF on Infiltration of Dendritic Cells during Early Left Ventricular Remodeling after Myocardial Infarction

“…These findings suggest that an inflammatory reaction is a prerequisite for the healing process. As the cause of inappropriate activation of the inflammatory response after MI, an autoimmune reaction is a possible mechanism relating to LV remodeling (11)(12)(13). Abbate et al reported infiltration of activated T cells into both infarcted and remote areas of the myocardium in patients with recent MI (1).…”